Tourette syndrome (TS) and disorders involving tic are highly prevalent and socially embarrassing. There are a group of TS sufferers with motor and vocal tics that are resistant to medication and behavioral intervention. Deep brain stimulation (DBS) has emerged as a highly efficacious treatment option for addressing motor and vocal tics in a select group of appropriately screened cases. The proposed research will directly address the important knowledge gaps in TS physiology and TS DBS. These gaps include a need to characterize the pathophysiological signals related to tics and the modulation of physiology by DBS therapy. In Aim 1, we will correlate individual tic expression with local fiel potential (LFP) activity in the human centromedian (CM) thalamic nucleus region and precentral gyrus (motor cortex) using next generation DBS devices capable of chronic LFP recordings. We will also study thalamocortical network interactions leading to tics. Our preliminary data from two subjects have revealed that low-frequency activity in the CM thalamus and beta rhythm suppression in the motor cortex correlate with the occurrence of tics, and that these features can be differentiated from the neural correlates of voluntary movements. In Aim 2, we will determine how LFP physiology changes following DBS therapy and clinical improvement. Our preliminary data from five subjects, treated with bilateral centromedian (CM) thalamic region DBS, (from recently completed NIH R34 and R21 grants) demonstrated the presence of both a measurable clinical effect and quantifiable physiological changes (decreases in low frequency power). Understanding how DBS modulates brain activity to reduce TS symptoms, could provide a neuromarker to guide clinical programming and potentially facilitate faster clinical relief. The overarching goal of the proposed project will be to generate the physiological dataset required to fill these knowledge gaps and to move the field toward responsive stimulation.